Is RELA p.Ile331Val (c.991A>G) pathogenic?

RELA p.Ile331Val (c.991A>G) is classified Uncertain significance in RELA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-13). AlphaMissense: ambiguous (0.3989); Very rare (popmax 0.000424%, nfe).

How common is RELA p.Ile331Val (c.991A>G) in the general population?

RELA p.Ile331Val (c.991A>G) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about RELA p.Ile331Val (c.991A>G)?

AlphaMissense predicts ambiguous (score 0.3989) — an in-silico prediction, not a clinical call.

RELA p.Ile331Val

c.991A>G · rs1180352560 · VCV1915152

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3989 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3989	ambiguous
REVEL	0.073	moderately benign-leaning
SaProt	LLR -4.65	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 1.9, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 4,007 bp · p 0.25 · regional, not allelic
Overall
CADD	20.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000424% European (non-Finnish) · 5/1,179,988 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,614,036 alleles · very rare exomes 5/1,461,870 · genomes 0/152,166 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: RELA
Protein: p.Ile331Val
Coding: c.991A>G
MANE Select: NM_021975
dbSNP: rs1180352560
Type: single nucleotide variant
Location: chr11:65655730 (GRCh38)
Gene constraint: LOEUF 0.4 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 73.52 · 88 PDB
Residue 331: the 'disordered' region; a UniProt-annotated variant site (found in a patient diagnosed with autoimmune lymphoproliferative syndrome; uncertain significance)

Full RELA gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RELA p.Arg198Ter Pathogenic/Likely pathogenic ★★ same type
RELA p.Arg236Ter Pathogenic/Likely pathogenic ★★ same type
RELA p.Arg329Ter Pathogenic/Likely pathogenic ★★ same type
RELA p.Gln372Ter Pathogenic/Likely pathogenic ★★ same type
RELA p.Ala264Val Uncertain significance ★★ ⚠ same type
RELA p.Ala404Pro Uncertain significance ★★ ⚠ same type
RELA p.Ala404Thr Uncertain significance ★★ ⚠ same type
RELA p.Ala538Thr Uncertain significance ★★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/rela-p-ile331val (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown